1. Field of the Invention
This invention relates to neurobiology and molecular biology. More particularly, this invention relates to methods for inhibiting suppression of long term potentiation, improving or increasing acute memory retention or spatial memory performance, and treating Alzheimer's disease by administering antagonists of PrPc, including PrPc soluble polypeptides, anti-PrPc antibodies and antigen-binding fragments thereof, soluble and fusion proteins thereof, and PrPc antagonist polynucleotides or aptamers. This invention further relates to pharmaceutical kits comprising, and methods for making and using, such combinations, as well as methods of identifying molecules that could function as PrPc antagonists.
2. Background Art
A pathological hallmark of Alzheimer's disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40-42 aa residues. Hardy & Selkoe, Science 297:353-356 (2002). Dementia in familial and sporadic AD is correlated with elevated concentrations of soluble Aβ42. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction. Lesne, et al., Nature 440:352-357 (2006); Haass & Selkoe, Nat Rev Mol Cell Biol 8: 101-112 (2007); Cleary et al., Nat Neurosci 8, 79-84 (2005); Chromy et al., Biochemistry 42: 12749-12760 (2003); Lacor et al., J Neurosci 27: 796-807 (2007); Lacor et al., J Neurosci 24: 10191-10200 (2004); Walsh et al., Nature 416: 535-539 (2002); Shankar, et al., J Neurosci 27: 2866-2875 (2007). At nanomolar concentrations, soluble Aβ-oligomers block long-term potentiation in hippocampal slices (Walsh et al., Nature 416: 535-539 (2002)) cause dendritic spine retraction from pyramidal cells (Lacor et al., J Neurosci 27: 796-807 (2007); Shankar, et al., J Neurosci 27: 2866-2875 (2007)) and impair rodent spatial memory (Lesne, et al., Nature 440:352-357 (2006)). Highly potent, soluble Aβ-oligomers have been prepared from chemical syntheses, from transfected cell culture supernatants, from transgenic mouse brain and from human AD brain. Lesne, et al., Nature 440:352-357 (2006); Chromy et al., Biochemistry 42: 12749-12760 (2003); Walsh et al., Nature 416: 535-539 (2002). Together, these data imply a high affinity cell surface receptor for soluble Aβ-oligomers on neurons, one that it is central to the pathophysiological process in AD.
While previous studies have provided direct evidence for the existence of a disease-mediating receptor, its identity has remained unknown. Here, we utilize expression cloning to reveal the cellular prion protein PrPc (hereinafter PrPc) as a high affinity receptor for Aβ-oligomers. Moreover, Aβ binds to a domain of PrPc which is implicated in neurodegeneration (Baumann, et al., EMBO J 26: 538-547 (2007); Li et al. EMBO J 26: 548-558 (2007)), and PrPc is required for Aβ-oligomer-induced synaptic dysfunction in vitro and in vivo. The identification of PrPc as a synapto-toxic receptor for the Aβ42-oligomers of Alzheimer's disease provides a novel site for the development of therapeutics designed to relieve Alzheimer's disease symptoms. Pharmaceutical compounds targeting PrPc may have higher specificity for the alleviation of synaptic dysfunction than those directed against other molecular targets.